U.S. patent number 4,097,578 [Application Number 05/734,557] was granted by the patent office on 1978-06-27 for 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl imidazolidines.
This patent grant is currently assigned to Roussel Uclaf. Invention is credited to Claude Bonne, Pierre Girault, Jacques Perronnet.
United States Patent |
4,097,578 |
Perronnet , et al. |
June 27, 1978 |
1-(3'-Trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl
imidazolidines
Abstract
Imidazolidines of the formula ##STR1## wherein X is selected
from the group consisting of oxygen and amine which inhibit the
effects of androgens on peripheric receptors without interfering
with normal hypophysial functions.
Inventors: |
Perronnet; Jacques (Paris,
FR), Girault; Pierre (Paris, FR), Bonne;
Claude (Bry-sur-Marne, FR) |
Assignee: |
Roussel Uclaf (Paris,
FR)
|
Family
ID: |
9161795 |
Appl.
No.: |
05/734,557 |
Filed: |
October 21, 1976 |
Foreign Application Priority Data
|
|
|
|
|
Oct 29, 1975 [FR] |
|
|
75 33084 |
|
Current U.S.
Class: |
514/389;
548/321.1; 548/321.5 |
Current CPC
Class: |
C07D
233/72 (20130101); A61P 43/00 (20180101); C07D
233/88 (20130101) |
Current International
Class: |
C07D
233/88 (20060101); C07D 233/72 (20060101); C07D
233/00 (20060101); A61K 031/415 (); C07D 233/72 ();
C07D 233/88 () |
Field of
Search: |
;260/309.5,309.7
;424/273 ;548/314 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Rhone-Poulenc Chem. Abst. 1973, vol. 79, No. 78805s..
|
Primary Examiner: Trousof; Natalie
Attorney, Agent or Firm: Hammond & Littell
Claims
We claim:
1. A compound of the formula ##STR3## wherein X is selected from
the group consisting of oxygen and imine.
2. A compound of claim 1 which is
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-5-imino-imidazoline-2-o
ne.
3. A compound of claim 1 which is
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione.
4. An antiandrogenic composition comprising an antiandrogenically
effective amount of at least one compound of claim 1 and an inert
pharmaceutical carrier.
5. A method of inducing antiandrogenic activity in warm-blooded
animals comprising administering to warm-blooded animals an
antiandrogenically effective amount of claim 1.
6. The method of claim 5 wherein the compound is
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-5-iminoimidazoline-2-on
e.
7. The method of claim 5 wherein the compound is
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione.
Description
STATE OF THE ART
British Pat. No. 997,037 described imidazolidines of a different
structure which have anti-epileptic and anticonvulsant
activity.
OBJECTS OF THE INVENTION
It is an object of the invention to provide the novel
imidazolidines of formula I and a novel process for their
preparation.
It is another object of the invention to provide novel therapeutic
compositions which inhibit the effects of androgens.
It is a further object of the invention to provide a method of
inducing anti-androgenic activity in warm-blooded animals.
These and other objects and advantages of the invention will become
obvious from the following detailed description.
THE INVENTION
The novel imidazolidines of the invention have the formula ##STR2##
wherein X is selected from the group consisting of oxygen and
imine. The compounds are
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione
and
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-5-imino-imidazoline-2-o
ne.
The novel process of the invention for the preparation of the
compounds of formula I comprises reacting 2-amino-2-cyano-propane
with 3-trifluoromethyl-4-nitrophenyl isocyanate in the presence of
a tertiary base to form
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-5-imino-imidazoline-2-o
ne which may be recovered or hydrolyzed in an acid media to obtain
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione.
The condensation is effected in the presence of a tertiary amine
such as pyridine, triethylamine or methyl ethyl pyridine and the
condensation is preferably effected in an organic solvent such as
tetrahydrofuran, ether or isopropyl ether. The acid for the
hydrolysis is preferably hydrochloric acid or sulfuric acid.
The novel antiandrogenic compositions of the invention are
comprised of an effective amount of at least one compound of
formula I and an inert pharmaceutical carrier. The compositions may
be in the form of injectable solutions or suspensions, tablets,
coated tablets, capsules, syrups, suppositories, creams, pomades
and lotions.
The excipient or pharmaceutical carrier may be aqueous or
non-aqueous vehicles, talc, arabic gum, lactose, starch, magnesium
stearate, cacao butter, fatty bodies of animal or vegetable origin,
paraffinic derivatives, glycols, preservatives, diverse wetting
agents, dispersants or emulsifiers.
The compositions due to their antiandrogenic activity without
interference with hypophysial functions are useful for the
treatment of adolescents without interfering with growth and for
the treatment of adults without the problems of chemical
castration. They are useful for the treatment of adenomea and
neoplasia of the prostate, of hirsutism, of acne, of seborrhea and
of hyperpilosity.
The novel method of the invention of inducing antiandrogenic
activity in warm-blooded animals, including humans, comprises
administering to warm-blooded animals an antiandrogenically
effective amount of at least one compound of formula I. The
compounds may be administered orally, rectally, topically,
perlingually or parenterally. The usual daily dose is 2 to 100
mg/kg depending on the method of administration and the compounds
.
In the following examples there are described several preferred
embodiments to illustrate the invention. However, it is to be
understood that the invention is not intended to be limited to the
specific embodiments.
EXAMPLE 1
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-5-iminoimidazoline-2-one
1 ml of triethylamine was added to a mixture of 49.6g of
3-trifluoromethyl-4-nitrophenyl isocyanate in 500 ml of
tetrahydrofuran and then 18 g of 2-amino-2-cyanopropane were
rapidly added thereto. The mixture was stirred for 72 hours at
20.degree. C and was evaporated to dryness under reduced pressure.
The residue was chromatographed over silica gel and was eluted with
an 8-2 methylene chloride-acetone mixture to obtain 27 g of
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4
-dimethyl-5-imino-imidazoline-2-one melting at 168.degree. C.
Analysis: C.sub.12 H.sub.11 F.sub.3 N.sub.4 O.sub.3. Calculated:
%C, 45.57; %H, 3.50; %N, 17.71. Found: C, 45.6; H, 3.6; N,
17.5.
IR Spectrum (chloroform): absorption at 3442 cm.sup.-1,
characteristic of NH; at 1755 cm.sup.-1, characteristic of C = 0,
at 1673 cm.sup.-1, characteristic of C = N; at 1615 and 1595
cm.sup.-1, characteristic of aromatic ring and at 1542, 1492 and
1355 cm.sup.-1, characteristic of NO.sub.2.
EXAMPLE 2
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione
A suspension of 10 g of
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-5-imino-imidazoline-2-o
ne, 35 ml of 22.degree. Be aqueous hydrochloric acid and 35 ml of
water was refluxed for an hour, cooled to 20.degree. C and poured
into water. The mixture was vacuum filtered and the recovered
precipitate was washed and dried to obtain 9.5 g of
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione
melting at 149.degree. C. A microanalytical sample after
crystallization from ethanol melted at 149.degree. C.
Analysis: C.sub.12 H.sub.10 F.sub.3 N.sub.3 O.sub.4. Calculated: %C
45.43; %H 3.17; %F, 17.96; %N 13.24. Found: C, 45.5; H, 3.4; F,
17.9; N, 12.9.
IR Spectrum (chloroform): absorption at 3438 cm.sup.-1
characteristic of NH; at 1792 and 1734 cm.sup.-1, characteristic of
C = 0, at 1613, 1597 and 1501 cm.sup.-1 characteristic of aromatic
ring and at 1545, 1358 and 1359 cm.sup.-1 characteristic of
NO.sub.2.
EXAMPLE 3
Tablets were prepared from 100 mg of the product of Example 2 and
sufficient excipient of lactose, starch, talc and magnesium
stearate for a final weight of 300 mg.
PHARMACOLOGICAL STUDY
Test A: Antiandrogenic activity in rats
This test was effected on groups of 5 male rats of the
Sprague-Dawley strain weighing 75 .+-. 5 g castrated by the scrotal
method while anesthesied with ether. The rats daily simultaneously
received subcustaneously for 7 days testosterone propionate at 50
.mu.g/rat/day and
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione
at 1 mg/day/rat. The products were in solution in a volume or 0.1
ml of sesame oil containing 5% of benzyl alcohol. The rats were
killed 24 method hours after the last administration and the
prostate and seminal vesicules were removed and placed for 24 hours
in an isotonic saline solution containing 10% formol. The organs
were then dissected and weighed to determine the inhibition of
weight increase of the genital organs induced by the androgen which
indicates the antiandrogenic activity of the test compound. The
variations of the weight of the prostate or seminal vesicules was
homogenized by logarithimic transformation by the method of
Bartlett [J. Roy. Stat. Soc., 1937, Supp. 4, p. 137] and this
homogeneity was verified by the Bartlett test [Biometrics, Vol. 3
(1947), p. 39]. The results were analyzed by factorial analysis and
are reported in Table I.
TABLE I ______________________________________ Weight of Weight of
Seminal Vesicules Ventral prostate Group in mg in mg
______________________________________ Controls 11.5 .+-. 0.9 16.8
.+-. 1.0 Testosterone 79.6 .+-. 8.1 90.3 .+-. 7.0 propionate Test
12.3 .+-. 0.8 15.0 .+-. 1.3 Compound Testosterone 17.2 .+-. 2.9*
45.0 .+-. 4.3* Propionate + Test Compound
______________________________________ *Factorial analysis
p.ltoreq.0.01
The data of Table I shows that the compound of Example 2 provokes a
92% inhibition of the weight increase of the seminal vesicules and
a 61% inhibition of weight increase of the prostate which indicates
good antiandrogenic activity against testosterone propionate.
The test was repeated with the product of Example 1 and the results
are reported in Table II.
TABLE II ______________________________________ Weight of Weight of
Seminal Vesicules Prostate Group in mg in mg
______________________________________ Controls 7.7 .+-. 0.7 11.9
.+-. 0.7 Testosterone 100.3 .+-. 6.1 105.6 .+-. 5.0 propionate
Compound of Ex. 1 10.9 .+-. 1.1 14.5 .+-. 0.4 Testosterone 29.1
.+-. 3.5* 66.3 .+-. 5.5* propionate + product of Ex. 1
______________________________________ *Factorial analysis p
.ltoreq.0.01
The results of Table II show that the product of Example 1 provoked
an inhibition of 77% of weight increase of seminal vesicules and a
43% inhibition of prostate weight increase which indicates good
antiandrogenic activity against testosterone propionate.
B. Inhibition of prostatic incorporation of radioactivity after
injection of a trace dose of H.sup.3 -testosterone in castrated
rats
Groups of 3 male rats of the Sprague-Dawley SPF strain weighing 70
.+-. 10 g were castrated 24 hours before receiving a subcutaneous
injection of 5 mg of the test product. 16 hours later, the animals
received an intramuscular injection of 10.mu. Ci/100 g of
1.alpha.-H.sup.3 -testosterone (26 Ci/mmol) in an alcoholic
solution and the animals were killed one hour after the hormone
injection. The ventral prostate was removed, rinsed with an
isotonic sodium chloride solution, weighed and then was solubilized
by alkaline digestion. The radioactivity of the samples were
measured after addition of 15 ml of sparkling liquid and the
results are reported in Table III as a percentage of inhibition of
testosterone incorporation. dpm/mg = disintegration per minute per
mg of fresh prostatic tissue.
TABLE III ______________________________________ Incorporation % of
Product dpm/mg Inhibition ______________________________________
Controls 114 .+-. 4 -- Example 2 35 .+-. 8 68 Example 1 80 .+-. 9
42 Controls 138 .+-. 8 --
______________________________________
The results of Table III show that the 2 products diminish the
incorporation of the hormone in the prostate.
Various modifications of the product and processes of the invention
may be made without departing from the spirit or scope thereof and
it should be understood that the invention is to be limited only as
defined in the appended claims.
* * * * *